Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence for sphingolipid metabolites such as ceramides and sphingosine- 1-phosphate (S1P) in the pathobiology of pulmonary disorders. To facilitate the translation of current in vivo and in vitro observations on the role of SphK1/S1P/S1PR2 in PAH pathobiology this proposal will explore the hypothesis that the SphK1/S1P/S1PR2 signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 will define molecular mechanisms by which SphK1 regulates the hypertensive response in animal and smooth muscle cell culture models. SA2 will define the role of S1P signaling via S1PR2 in regulating pulmonary hypertension in animal and smooth muscle cell models. SA3 will conduct association studies to link SNPs within S1P biosynthetic/signaling pathway genes with susceptibility to PAH. SA4 will evaluate SK1 and S1PR2 antagonism as potential therapeutic strategies in PAH. The ultimate goal of this proposal is to lay the foundation for the development of novel therapeutic targets for PAH.